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13th Conference on Retroviruses and Opportunistic Infections


Denver, Colorado - February 5-8, 2006



ESCAPE FROM AN IMMUNODOMINANT EPITOPE IN HLA-B27-POSITIVE INDIVIDUALS PREDICTS VIRAL LOAD OUTCOME

Conf Retrovir Opportunistic Infect 2006 Feb 5-8;13:abstract no. 429

Palanee Ammaranond1,2, K Petoumenos1, M Middleton1, N Doong3, R Finlayson4, M McMurchie5, D Van Bockel1,2, D Cooper1,2, J Kaldor1, A Kelleher1,2, and on behalf of the Australian LTNP Study Group
1Natl Ctr in HIV Epidemiology and Clin Res, Univ of New South Wales, Sydney, Australia; 2St Vincent's Hosp, Sydney, Australia; 3Burwood Practice, Sydney, Australia; 4Taylor Square Private Clin, Sydney, Australia; and 5407 Doctors, Sydney, Australia


BACKGROUND: Despite significant literature on HIV escape from cytotoxic T-lymphocyte (CTL) responses, a definitive association between escape and disease progression has never been demonstrated. The immune response in HLA-B27+ individuals is characterized by an immunodominant response to a conserved epitope in gag p24 (KRWIILGLNK, aa 263-272) and is associated with long-term non-progression (LTNP). Substitutions at position 264 of this epitope have been identified as escape mutations. We hypothesized that escape at this immunodominant epitope would be a significant determinant of disease progression.

METHODS: We identified 19 HLA-B27+ patients from the Australian LTNP cohort, with an average follow-up of 16 years after infection. Gag, nef, and env regions were sequenced from plasma RNA at multiple time points until the last time point available or the visit on which individuals started ART. Host genetic factors affecting disease progression were determined, and univariate and multivariate analyses were performed for potential confounding factors.

RESULTS: Of 19 HLA-B27 LTNP, 12 had wild type sequences at the immunodominant epitope at all time points, and 7 carried CTL escape variants: R264K (n = 3), R264G (n = 3), or R264Q (n = 1). A comparative analysis between the wild type and escape groups was performed. Median viral load and CD4+ T-cell counts were not significantly different between these groups at enrollment to the cohort. At last visit, viral load was 1750 and 21,000 RNA copies/mL in the 2 groups, respectively (p = 0.01). Median CD4+ T-cell counts were 596 and 360 cells/µL, respectively (p = 0.06). Time-weighted change in area under the curve revealed higher viral load in the escape group (p = 0.01), but no difference in CD4+ T-cell counts (p = 0.5). Escape mutants at other HLA-B27 epitopes in p17, gp41, and nef were uncommon and did not segregate. None of the 19 carried a nef-deleted virus. The host polymorphisms associated with alterations in disease progression-CCR5Δ32, CCR2-64I, and SDF1-3’A-did not segregate to either wild type or escape groups. Each of these host and viral factors was examined for a relationship to viral load. The presence of a SDF1-3’A mutation was associated with lower viral load (p = 0.01).

CONCLUSIONS: The presence of the escape mutant and lack of the SDF1-3’A mutation were found to be independently related to higher viral load at the last visit. Escape is a major determinant of viral load in HLA-B27+ individuals.

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2006-02-05
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Copyright © 2006 - Foundation for Retrovirology and Human Health. Reproduction of this abstract (other than one copy for personal reference) must be cleared through the Foundation for Retrovirology and Human Health.